HORMONAL REGULATION OF CARCINOGENESIS IN TROUT

Project Details

Description

DESCRIPTION: Sex hormones andpituitary hormones are known to modify chemical carcinogenesis in mammals.The hormones may act at the initiation stage or at the promotion stage ofcarcinogenesis. In rainbow trout, 17 beta-estradiol has been shown to be apromoter of aflatoxin B1-induced carcinogenesis. However, in this species,little or no information is available regarding the effects of hormonesespecially those of pituitary origin at other stages of chemicalcarcinogenesis. Can hormones modify the activation and detoxication ofcarcinogens in trout as in mammals? Can the binding of carcinogens totrout liver DNA be modified by hormone pretreatment? These are some of thequestions to be addressed in this project. The applicant hypothesizes thatin the rainbow trout different peptide hormones and glucocorticoids affectthe metabolism and covalent binding index of carcinogens by regulating theexpression and activities of enzymes involved in activation anddetoxication of chemical carcinogens. This hypothesis will be tested bycarrying out experiments with the following specific aims: 1) Examine theeffect of in vivo administration of ACTH, gonadotropin, thyroxine, growthhormone, and cortisol on the in vitro metabolism of aflatoxin B1 (AFB1),dimethylnitrosamine (DMN), and 7,12-dimethylbenz(a)anthracene (DMBA) bymicrosomal and mitochondrial preparations of liver and head kidney fromrainbow trout. 2) Determine whether the hormones affect the expression ofcytochrome P450 mRNAs or P450 isozymes involved in AFB1, DMN, and DMBAmetabolism in trout liver. 3) Determine the influence of glucocorticoidsand growth hormone on the induction of hepatic cytochrome P450 in trouttreated with beta-napthoflavone ( BNF); dexamethasone or pregnenolone 16beta-carbonitrile (PCN); or phenobarbital (PB). 4) Determine the effect invitro of cortisol on the hepatic microsomal cytochrome P450 dependentmetabolism of AFB1, DMN, and DMBA in trout. 5) Determine the role ofhormones on the levels and activities of cytosolic and microsomalglutathione S-transferase (GSH-t) in trout liver. 6) Determine the effectof the hormones on the excretion and in vivo binding of AFB1, DMN, and DMBAto DNA and protein in liver of trout. 7) Assess the effect of hormones onhepatic tumor incidence in trout given AFB1. These studies should providethe necessary information regarding the role of hormones on chemicalcarcinogenesis in trout and should improve out understanding of some of themechanisms by which hormones modify carcinogenesis in this animal model.